Selectivity profiling of novel indene H1-antihistamines for the treatment of insomnia

A series of indene analogs of the H1-antihistamine (−)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H1-antihistamines with desirable selectivity over CYP enzymes, the M1 muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.

Structure–activity relationships were conducted around a lead H1-antihistamine 2, to identify selective analogs with the potential for reduced biotransformation through the CYP2D6 pathway. A number of candidate compounds were identified from the general structure 4 using the appropriate combination of electron rich heterocycles, the presence of a chiral center and 6-substitution in the indene core.Figure optionsDownload as PowerPoint slide